Diuretics Flashcards
Main site of action for diuretics
lumenal (urine) surface of renal tubule cells
Mechanisms of diuretics
·Interactions with membrane transport proteins (thiazides, furosemide, triamterene) • Specific interactions with enzymes (acetazolamide) or hormone receptors (spironolactone) • Osmotic effects preventing water reabsorption (mannitol)
How do diuretics affect Na?
Do NOT act at Na/K pump. Diuretics decrease Na reabsorption
Which diuretics act at the proximal convoluted tubule?
Carbonic anhydrase inhibitors,
Which diuretics act at loop of Henle
High Ceiling Diuretics
Which diuretics act on distal convuluted tubule?
Thiazide diuretics
Which diuretics act on the collecting tubules?
Potassium sparing diuretics: Aldosterone antagonists and Na-channel blockers
Proximal convoluted tubule reabsorption
Almost all metabolites and 60-70% Na is reabsorbed here.
What does Carbonic anhydrase do and where is it located? -not on test
CA is on luminal surface of proximal convoluted tubule. Allows for reabsorption of HCO3- and exchanges H for Na (Na is reabsorbed and H is excreted into urine)
Carbonic anhydrase inhibitors- example and MOA -not on test
Acetazolamide. Inhibits CA enzyme
Carbonic anhydrase inhibitors-clinical uses and toxicities - not on test
Not used in HF. Used for glaucoma and acute mountain sickness (slow progression of pulmonary or cerebral edema). Toxicity: increased urinary pH, K+ wasting
Function of Loop of Henle
Water removal from lumen ccurs in descending limb. Active NaCl reabsorption occurs in ascending limb via Na-K-2CL cotransporter.
Loop of Henle agents (High ceiling diuretics)- examples
Furosemide, torsemide and bumetanide
High ceiling diuretics MOA
Inhibit NaCl transport (Na+-K+-2Cl–transporter) in thick ascending limb of loop of Henle. This results in increased Mg and Ca excretion into lumen to offset the lumen positive potential
High ceiling diuretics pharmacokinetics
Rapid oral absorption. Renal secretion and filtration
High ceiling diuretics clinical use in CHF
Preferred diuretic class b/c efficiency. Used in HF patients with volume overload to eliminate pulmonary congestion and peripheral edema. Enhanced with salt restrictions. Furosemide most commonly used.
Why do HF patients have reduced diuretic response?
decreased drug delivery to kidney due to decreased Renal Blood Flow and hypoperfusion activation of RAAS and SNS
Additional uses of high ceiling diuretics besides HF
Acute pulmonary edema, refractory edema, Hypercalcemia
Explain drug combos commonly used in refractory edema
High ceiling diuretic can be combined with Thiazide (blocks distal tubule Na reabsorption which is sometimes increased with high ceiling due to increased Na delivery to this segment), or Aldosterone antagonists to improve survival and ameliorate K wasting.
High ceiling diuretics adverse reactions
Hypokalemic metabolic alkalosis via enhanced secretion of K+ and H(can cause ectopic pacemakers), ototoxicity,Hyperuricemia/hyperglycemia, hypomagnesemia
Loop diuretic effect on plasma electrolytes- efficacy, K, H, Ca, Mg, Urate
high efficacy, decreased K, decreased H, decreased Ca, decreased Mg, increased urate
Function of distal convoluted tubule
Na/Cl co transporter facilitates reabsorption of NaCl. Also site of active Ca reabsorption via Na/Ca exchanger which is regulated by parathyroid hormone
Thiazide examples
Hydrochlorothiazide - Chlorthalidone - Metolazone
Thiazide MOA
inhibiting the Na+/Cl- cotransporter and increasing urinary excretion of NaCl (modest diuretic effect, only 5-10% of filtered Na+ is reabsorbed here). Increases reabsorption of Ca
Thiazide pharmacokinetics
All abosorbed orally. • Hydrochlorothiazide: Prototype thiazide, twice daily dose • Chlorthalidone - Metolazone: longer durations → once daily dosing. May precipitate gout attack due to secretion by organic acid secretory system
Thiazide clinical uses
CHF: Synergistic effect with loop diuretics. Hypertension (first line) and Hypercalcuria (decreases incidence of kidney stones)
Thiazide adverse rxns
Hypokalemia (ectopic pacemakers), Hyperglycemia, hyperuricemia, hyperlipidemia
Effect of thiazide on plasma electrolytes: efficacy, K, H, Ca, Mg, Urate
mid-high efficacy, slightly decreases K, slightly decreases H, increases Ca, increases urate, no change to Mg
What part of the kidney does aldosterone target? What does aldosterone do?
Collecting tubules- aldosterone increases number and activity of Na and K channels, and Na/K pump
function of collecting tubules
Only 2-5% of NaCl reabsorption occurs at this site. Na and K transport occur in principal cells via channels and Na/K pump (K excretion is coupled to Na reabsorption).
Aldosterone Antagonists examples
Spironolactone / Eplerenone
Na+-channel Blockers xamples
Triamterene / Amiloride
Aldosterone antagonists MOA
Competitive antagonist at aldosterone receptor, binds to cytosolic receptor preventing enhancement of protein synthesis. Prevents Na reabsorption which makes lumen more positive, thus less K and H move into urine. Only mild diuresis
Na channel blocker MOA
Direct effect to block the Na+-channels on collecting duct lumen to decrease Na+ reabsorption (and thus decreases coupled K+ secretion)
Pharmacokinetics of spironolactone, eplerenone, triamterene/amiloride
Spironolactone: 1-2 doses/day; poor oral absorption. Slow onset of action. • Eplerenone : 1-2 times/day orally, metabolized by CYP3A4.
• Triamterene / Amiloride: Triamterene metabolized in liver, amiloride excreted unchanged thus given less frequently. Effect within 2-4 hrs, but 1-3 days to maximal effect.
Clinical uses of K sparing diuretics
CHF, Hyperaldosteronism (spironolactone and eplerenone), Hirsutism of polycystic ovary syndrome via block of androgen receptor (spironolactone), hypertension (in combo with thiazide)
Clinical use of K sparing diuretics in CHF
Aldosterone antagonists improve survival by blocking aldosterone receptors on heart rather than kidney. Anti-remodeling action prevents hypertrophy induced by aldosterone. Raises serum K to counter K wasting diuretics
Adverse rxns of K sparing diuretics
Hyperkalemia, endocrine abnormalities (spiro)
